PROJECT SUMMARY Clinical trials suggest that nebivolol reduces the risk of cardiovascular events and improves hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF), but its efficacy in patients with pulmonary hypertension (PH) and HFpEF is unknown. The Candidate's long-term goal is to develop an independent research career in translational pharmacogenomics, using novel analytical techniques to improve the treatment of PH through increased personalization of therapy. The objective for this proposal is to evaluate the therapeutic efficacy and associated genomic underpinnings of nebivolol response in patients with PH associated with HFpEF. The central hypothesis is that nebivolol will decrease PH severity in patients with HFpEF, and this response can be predicted by a genomic signature, which corresponds to functional genetic polymorphisms. The rationale for the proposed research is that a genome-based understanding of the therapeutic efficacy of nebivolol for HFpEF-associated PH is likely to contribute to a framework whereby new approaches for treatment can ultimately be developed, while at the same time, helping to establish the Candidate's independence as a translational pharmacogeneticist. To test the central hypothesis and accomplish the objective for this application, the Candidate will pursue the following two specific aims: 1) Evaluate the therapeutic efficacy of nebivolol for PH associated with HFpEF; and 2) Determine genomic underpinnings of nebivolol responsiveness in patients with PH associated with HFpEF. Under the first aim, the primary approach will entail a proof of principle clinical trial, where hemodynamics will be tested before and after four months of daily oral nebivolol treatment. For the second aim, the approach will involve a genome-wide microarray expression analysis, comparing expression patterns with hemodynamic response to nebivolol, as well as a cis-eQTL analysis to correlate nearby polymorphisms to the genes of interest. The proposed research is potentially innovative because it departs from the status quo by focusing on a ?-blocker with potentially beneficial pleiotropic effects, nebivolol, for treatment of the acual PH. In addition, the Candidate will focus on identifying a genomic signature of nebivolol response, thus providing data for further personalization of nebivolol therapy. The proposed research is significant because it is expected to contribute meaningfully to the future development of treatments for a disease category that currently has no established treatments. Ultimately, the results from this project are expected to have an important positive impact in that they will provide important proof of principle for the continued development and future clinical trials of nebivolol as a novel approach for treatment of PH associated with HFpEF. In order to attain his long-term goal and the objective for this proposal, the Candidate will require training n clinical trial execution, genome-wide expression analyses, and bioinformatics. Such training, which complements existing expertise in cardiovascular pharmacogenetics and clinical pharmacy, will be achieved through a combination of highly focused coursework, significant hands-on research experience, and active mentored training. The Candidate's mentoring team possesses all the necessary knowledge and skills, including a history of successfully training early-career faculty, for success. Dr. Roberto Machado, Primary Mentor, offers expertise in translational pulmonary research, particularly in PH. Specifically, his research focuses on genomic characterization of pulmonary endothelial function in patients with PH and development of small molecule therapeutics. He is a past K awardee and currently is PI of an R01 grant in the area of the Candidate's project. Dr. Julie Johnson, Primary Mentor, provides expertise in cardiovascular pharmacology and pharmacogenomics. She is currently PI of two U01 and one R01 grants. Neil Bahroos, an expert in biomedical informatics provides necessary expertise in bioinformatics and data analysis. Apart from the three primary mentors, the Candidate has also created an Interdisciplinary Advisory Committee, which will include the primary mentors, but also other advisers with specific expertise to complement those of the mentors. The Advisory Committee will meet quarterly to assess the Candidate's progress, and provide guidance for future research pursuits, as well as professional development and training in the responsible conduct of research. The environment at the University of Illinois at Chicago (UIC) is an ideal setting for the Candidate to acquire research independence in the area of pulmonary pharmacogenomics. In particular, UIC groups such as the Institute for Human Genetics and Center for Clinical and Translational Sciences provide excellent resources for collaboration and career development. Additionally, UIC core laboratories have the necessary state-of-the-art equipment and expertise needed to assist the Candidate in the proposed genomic studies. Importantly, the institutional signing official, Dr. Jerry Bauman, commits all necessary university equipment, facilities, and resources to the Candidate and his career development during the period of the award. This includes a commitment of at least 75% of the Candidate's time for research career development. In summary, the Candidate's demonstrated previous training and experience, innovative research plan, high-quality training plan, outstanding mentorship team, and supportive research environment foretell success in acquiring research independence under the proposed award.